2. Academic Validation
  3. Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy

Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy

  • Am J Hum Genet. 2017 Jan 5;100(1):169-178. doi: 10.1016/j.ajhg.2016.11.017.
Satoko Miyatake 1,  Satomi Mitsuhashi 2,  Yukiko K Hayashi 3,  Enkhsaikhan Purevjav 4,  Atsuko Nishikawa 5,  Eriko Koshimizu 6,  Mikiya Suzuki 7,  Kana Yatabe 7,  Yuzo Tanaka 7,  Katsuhisa Ogata 7,  Satoshi Kuru 8,  Masaaki Shiina 9,  Yoshinori Tsurusaki 6,  Mitsuko Nakashima 6,  Takeshi Mizuguchi 6,  Noriko Miyake 6,  Hirotomo Saitsu 10,  Kazuhiro Ogata 9,  Mitsuru Kawai 7,  Jeffrey Towbin 4,  Ikuya Nonaka 11,  Ichizo Nishino 11,  Naomichi Matsumoto 12
Affiliations

Affiliations

  • 1 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa 236-0004, Japan.
  • 2 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Genome Medicine Development, Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Biomedical Informatics Laboratory, Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
  • 3 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Pathophysiology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan.
  • 4 Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
  • 5 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; Department of Education, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
  • 6 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
  • 7 Department of Neurology, National Hospital Organization Higashisaitama Hospital, Hasuda, Saitama 349-0196, Japan.
  • 8 Department of Neurology, National Hospital Organization Suzuka National Hospital, Suzuka, Mie 513-8501, Japan.
  • 9 Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
  • 10 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
  • 11 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan.
  • 12 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan. Electronic address: [email protected].
PMID: 28017374 DOI: 10.1016/j.ajhg.2016.11.017
Abstract

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.

Keywords

MYPN; congenital myopathy; intranuclear rod myopathy; nemaline myopathy; whole-exome sequencing.

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